The adenovirus was first described as a unique antiviral agent in 1953 by Rowe et al., while attempting to establish cell cultures of tonsil and adenoid tissue. Rowe discovered that a transmissible agent was destroying the epithelial cells.
Now, it is recognized that adenovirus very often cause respiratory tract diseases. However, depending on the infecting serotype, they may also cause other diseases such as for example gastroenteritis, conjunctivitis, cystitis, hepatitis and exanthema. In the case of certain serotypes, the clinical condition depends on the place of infection, for example serotype 7, acquired by inhalation, and is associated to severe lower respiratory tract diseases, while oral transmission of the same serotype causes asymptomatic infection or slight disease.
Adenoviruses are endemic in pediatric population, and it has been reported that they are the cause of up to 10% of the total infections of the respiratory tract, causing 10% of declared cases of acute gastroenteritis (Rachel Y, Moon M D. Adenovirus infections. Pediatrics in review 1999; 20:230-2).
Adenoviruses are transmitted by direct contact, by fecally-orally, by inhalation and occasionally by stagnant water. They prefer especially epithelial cells, affecting almost all mucosa. They are DNA viruses, belonging to the family Adenoviridae and genus Mastadenovirus (Fener F.: Classification and nomenclature of viruses. Intervirology 1976, 1-115).
Human adenoviruses are divided into 6 designed genders and classified from A to F, based on their ability to agglutination and are also subdivided into 47 serotypes, about 33% of which are related to some disease (Hierholzer J, Wigand R, Anderson L, et al. Adenoviruses from patients with AIDS: A plethora of serotypes and a description of five new serotypes. J Infect Dis 1998; 15:804-13; Horwitz M. Virology. 2nd ed New York: Reven Press: 1990)
Adenoviruses are a frequent cause of respiratory tract in infants, but many of these infections are subclinical or result in slight diseases. However, in some cases they cause severe illness (Andrew S, Day D, Mc Gregor D. Fatal adenoviral disease in siblings. Pediatr Infec Dis J 1998; 17:83-5.). The spectrum of clinical manifestations of the different serotypes of adenovirus is very broad and many times they superimpose.
Adenoviruses type 40 and 41 are an important cause of diarrhea in infants under 2 years old (Uhnoo I, Wadell G, Svensson L, et al. Importance of enteric adenoviruses 40 and 41 in acute gastroenteritis in infants and young children. J Clin Microbiol 1998; 20:365). Diarrhea and vomiting are the predominant symptoms in enteric infections by adenoviruses, as they appear in 97% and 79% of the infants respectively, with an average duration of 9 to 12 days.
The adenovirus type 7 is a recognized cause of severe disease in infants, and the effect may include chronic pulmonary disease such as bronchiectasiae and bilateral hyperlucent lung. Severe pneumonia by adenovirus has been associated to immunosupression, malnutrition or recent severe viral infection (Andrew S, Day D, Mc Gregor D. Fatal adenoviral disease in siblings. Pediatr Infec Dis J 1998; 17:83-5.).
In general, symptoms expressed by the adenovirus depend on the infecting serotype and the target affected organ/s, while its aggressiveness is inversely related to the host immunological condition.
The adenovirus can also cause acute follicular conjunctivitis. This may be the most frequent and benign adenoviral infection of the eye, it is generally unilateral and it is expressed by follicular injuries on the conjunctival surface. Symptoms are characterized by burning in the eye, sensation of a foreign matter and conjunctival erithema, resolving in a term of about 10 days to 3 weeks. An infant form of the epidemic keratoconjunctivitis has been described, affecting unweaned babies under 2 years old. Normal pseudo membranous conjunctivitis is accompanied by fever, pharingitis, otitis, diarrhea and vomiting (Mandell G, Bennett J, Dolin R. Principles and practice of infectious disease 5a Ed, Philadelphia: Churchill Livingstone 2000.).
The epidemic keratoconjunctivitis is an infectious process of viral nature, which is characterized by affecting the conjunctiva, with secretions and infiltrations of the cornea of nummular aspect. Due to its infectious nature, there may be a tumefaction of pre-auricular lymph nodes.
As its name indicates, in the epidemic keratoconjunctivitis there is a joint affectation of the cornea and conjunctiva due to, in general, the infection by adenovirus serotype 8, 19 y 37. However, it has also been described that, though with less frequency, serotypes 2-5, 7, 9, 10, 11, 14, 16, 21 and 29 can also be the cause of this disease.
Epidemic keratoconjunctivitis is highly contagious. Preferably it affects adults that occasionally also present generalized symptoms in the form of general malaise, odynophagia and febricula. It presents a very acute onset with an important sensation of foreign matter, conjunctival and palpebral edema, mixed hyperemia and abundant tearing. All these symptoms rapidly progress and attain their maximum intensity at the third day. After the first 24 hours, follicles in the conjunctiva can be observed. Secretion, that at the beginning is waxy, turns into serofibrinous that may evolve into the formation of pseudomembranes. Between the third and fifth day, the condition bilateralizes, though contralateral affection of the eye is always slighter than in the first day. In 80% of the cases there appears superficial punctate keratitis visible with a slot lamp and after instillation of fluorocein. These lesions are resolved in a term of at least 15 days. This period is longer is subepithelial immunocomplexes are deposited, above the Bowman's layer. Thus opacificities impairing vision and that take to reabsorb a variable period of time that ranges from months to even years.
Epidemic keratoconjunctivitis uses to be a frustrating entity for the patient and physician, as so far no pharmaceutical to fight the adenovirus itself has been developed. Today, when keratoconjunctivitis is diagnosed, generally it is prescribed a symptomatic therapy based on artificial tears, lubricants and non-steroid anti-inflammatory agents, which can only improve the discomfort associated to this condition. Though corticosteroids can decrease the severe inflammation observed in some cases, they can also extend the clinical course of the disease, sometimes developing even subepithelial infiltrates.
Moreover, the infections caused by the herpes simplex virus (HSV) are widely disseminated in the human population, and this is the only natural reservoir of said virus. The herpes simplex virus type 1 (HSV-1) induces an ocular disease in humans called herpetic stromal keratitis (HK), as a consequence of an inflammatory reaction that occurs in the human eye in response to the infection (Cloaue C P M, Menage M J, Easty D L. Severe herpetic keratitis. I: Prevalence of visual impairment in clinic population. British J. Opthalmol. 1988; 72:530-33). The HK is the main cause of blindness in the industrialized countries and the first cause of cornea transplant.
Studies in animal models have been very useful to reproduce and characterize evolution of the infection induced by HSV-1, resulting in a pathology associated to the acute and recurrent disease ([Minagawa H, Sakai Y, Li Y, Ishibashi T, Inomata H and Mori R.: Suppression of infectious virus spread and corneal opacification by the combined use of recombinant interferon beta and interleukin-10 following corneal infection with herpes simplex virus-1 in mice. Antiviral Res. 1997; 36: 99-105). Thus, the murine model of ocular infection induced by HSV-1 constitutes a suitable alternative to test antiviral drugs in vivo as it allows to reproducing the man pathology (Brandt C R, Coakley L M and Grau D R. A murine model of herpes simplex virus-induced ocular disease for antiviral drug testing. J. Virol. Methods 1992; 36:209-22).
The present inventors have synthesized novel compounds that show anti-inflammatory and antiviral properties, which are especially efficient to treat diseases caused by adenoviruses and/or herpes simplex type 1. Particularly, the compounds of the present invention are particularly useful for preparing ophthalmic pharmaceuticals to treat diseases caused by adenovirus and preferably, epidemic keratoconjunctivitis. Also, particularly, the compounds of the invention are especially useful for preparing ophthalmic pharmaceuticals for the treatment of diseases caused by the herpes simplex virus type 1 (HSV-1) and preferably, herpetic stromal keratitis (HK).